Advances in Therapeutic Vaccines Against HPV: A Review of Human Clinical Trials

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This review of HPV therapeutic vaccines is a quite straight forward cataloguing of clinical trials that have assesses HPV DNA clearance as an endpoint.  I like the time line in Fig 2, however I wish that more commentary and perspective was provided.  Example of critical topics in the development of HPV therapeutic vaccine that could be addressed are 1) the potential effector mechanism(s), 2) issues with measuring them in cervicovaginal tissue, 3) the pros and cons of using virus clearance vs histological regression as the primary endpoint in the trials, 4) the distinction that should be made between trials of CIN2+ vs CIN3, since CIN2 has a higher rate of spontaneous regression, 5) the potential advantages/disadvantages of protein, nucleic acid, and vector based approaches, and 6) why has there been modest progress in the past 20-30 years, despite extensive efforts, and what might be done to increase it.

Specific points in the text:

1. Line 47: HIV infection is thought to primarily promote persistence of HPV infection, not its initial acquisition.
2. Line 51: it was already stated above (line 47) that HIV is a key factor in HPV-associated cancers.
3. Line 62: change to “naked icosahedral structures”.
4. Line 65: E6/E7 are not highly expressed in HR infections, at least not in the lower levels of the epithelium that are under immune surveillance. They are more highly expressed in cancer.
5. Line 74: sexual risk behaviors are not generally considered independent risk factors for CC progression, independent of HPV infection.
6. Line 80: change “latently” to “asymptomatically”. “Latent” is usually reserved for infections in which HPV DNA cannot be routinely detected.  Most of the infections under discussion here will be readily detected in standard DNA amplification tests.
7. Line 121: The composition of Papilocare needs to be briefly presented.
8. Line 145: what are some of these distinct advantages and drawbacks?
9. Line 182: although indicated in the Table, the fact that BPV1 E2 was used in the vaccine should be mentioned. Also, that, unlike all the other vaccines, this vaccine is administered by intralesional infection.  It’s an oversight that method of delivery of these vaccines is not mentioned anywhere in the text.   
10. Line 184-187: I find this statement a bit strident. Although the vaccines should be designed for implementation LMICs, there isn’t a compelling reason that initial clinical trials should be performed there.  In fact’s there have been arguments made that interventions developed by companies in high income countries should first be tested there, and not place the burden on low resource settings were state of the art follow up of serious adverse events are likely to be more challenging.
11. Line 207: E6 and E7 are predominantly nuclear proteins and so there is no reason to believe that antibodies to them would play any effector role in regression. At best they are biomarker for the induction to T helper responses.
12. Line 219: I don’t understand the meaning of the statement “As LMICs are far from the targets proposed by WHO”. WHO has recently published a preferred product document for HPV therapeutic vaccines that emphasized the need to develop candidates with global potential.  See: (https://www.who.int/publications/i/item/9789240092174
13. Line 225: Making the unqualified statement that “therapeutic vaccines have been shown to be effective” seeming implies that the reason that none have commercialized is due to factors other than efficacy, when in fact insufficient efficacy is the primary reason that we don’t have any on the market.

Specific comments on the Table:

1. I suggest adding a column reporting the number of doses administered in each protocols. One of the keys for practical delivery in low resources settings is limiting number of doses.
2. In the “Clearance Results” column, it seems important to indicate the duration of trials since the number spontaneous clearance will increase over time.
3. Ref 32: It would be preferable to report the total virologic clearances here. Restricting to histologic clearance here and not elsewhere give a false impression of exceptional efficacy.
4. Ref 34: “V7” and “V8” have no intrinsic meaning.  The time since vaccination should be reported.  Also specify whether these ORs were relative to a placebo control or historical data.
5. Ref 36: there were 54 women in the trial. Why was 34 used as the denominator in the next column?
6. Ref 37: no date provided.
7. Ref 41: column 2, what is the composition of this vaccine?
8. Ref 42, 43: what is the denominator for the 3 clearances? The participants in one of the trials or both?
9. Ref 44: see comment #4.
10. Ref 46: I don’t understand why the statement about inability to distinguish vaccine-mediated vs spontaneous clearance is specifically inserted here. Isn’t this true of all the trials?
11. Ref 48: “negativization” is not in general English usage.
12. Ref 49: As in #10, I don’t understand why the comment about needing to improve efficacy is specifically stated here. Isn’t this true for all the vaccines?

 

Author Response

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Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The paper by Elena Martin et al., entitled “Advances in Therapeutic Vaccines Against HPV: A Review of Human Clinical Trials” provides the review of 18 trials on HPV therapeutic vaccine in patients with high-risk papillomavirus-associated intraepithelial lesions.

The study is well conducted, most of the study available have been carefully analyzed and their main characteristic well presented in the table 1.

However, the main conclusion of this review is somewhat deceptive. The authors observe that “although therapeutic vaccines demonstrate promising immunogenicity and preliminary efficacy, none are yet approved for commercial use (a well-known fact). Variability in study designs and endpoints underlines the need for standardized protocols and further phase III trials (obvious). Advancing this field may significantly enhance cervical cancer control efforts” (is this last sentence really necessary?).

As presented the conclusion of the abstract is not very incentive for potential readers to get deeper into the text. In other words, could the authors help the readers to have a better view of what is going on? For instance, many of the trials have been reported more than 10 years ago and did not gave support to further developments while others provided better results and are still under investigations. Is it possible, in the discussion, to make this important difference? Is it possible to provide approximatively the rate of expected efficiency? To have an idea of the term before consolidated data might be available? Using which technology? If this supplementary comments could be provided, the conclusion of the abstract would be more positive and the authors would have more precisely achieved their goal of providing a critical view on this important topic.

Author Response

Please see the attachment

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

Thank you for the modifications of the manuscript that improve the quality of this interesting review/